Cadherins are calcium-dependent cell adhesion that play pivotal roles in the specification of embryonic cells and their segregation into functionally distinct groups. They operate by connecting cells expressing the same cadherin type through a homophilic binding mechanism, and require interactions on both sides of the membrane for this function. In the nervous system, cadherins are expressed by e distinct axon populations, and are implicated to regulate neuronal specificity. Cadherin molecules have recently been localized in synaptic junctions, and are suggested to play a role in synapse specification and plasticity. This project will investigate in the hippocampal formation the function and mechanism of operation of T-cadherin that is anchored to the membrane through a glycosylphosphatidyl anchor. T-cadherin is discretely localized in hippocampal laminae where axons and dendrites interact to form synaptic contacts. This suggests that T-cadherin plays a distinct role in axonal interactional interactions either during axon guidance and target selection, and/or at synapses. Using mice deficient for T-cadherin gene function, this project will investigate the function of T-cadherin in the establishment of hippocampal circuitry. First, we will determine if T- cadherin is a component of synaptic junctions, and how its expression relates to that of the classical cadherins that are expressed in synapses in areas of T-cadherin expression. Second, we will address the role of T- cadherin in axonal interactions of mossy fiber axons during pathfinding and synapse formation in the stratum lucidum in T-cadherin-deficient mouse mutants. Third, we will dissect T-cadherin's role in neuronal differentiation and synapse formation in an in vitro model. Lastly, we will begin to analyze the mechanism of T-cadherin's function by characterizing proteins associated with T-cadherin. This work will contribute to the molecular understanding of the mechanisms underlying the formation of the intriguing neuronal circuitry involved in cognitive functions.